The hallmark feature of Neurofibromatosis type 1 (NF1) is the development of multiple benign peripheral nerve sheath tumors (PNST), also known as neurofibromas, in the peripheral nervous system (PNS). One neurofibroma subtype, plexiform neurofibroma, can arise in functionally critical nerves and diffusely infiltrate through the nerves, causing neurological problems that only rarely can be cured by surgery. Moreover, plexiform neurofibroma is the only neurofibroma subtype with the potential to undergo malignant transformation and progress to malignant peripheral nerve sheath tumors (MPNSTs). MPNST is a major cause of death in individuals with NF1, particularly for those younger than 40 years of age. These PNS cancers are resistant to conventional chemo- and radiotherapies. Furthermore, the typical deep location in the body and locally invasive growth often prevent complete surgical resection of MPNSTs. Consequently, the 5-year survival rate of all ages with NF1 and MPNSTs is poor, approximately 21%. Together, these clinical observations emphasize the urgent need for novel therapies based upon a greater understanding of the molecular and cellular mechanisms that underlie NF1- associated plexiform neurofibromas and MPNSTs. We recently have developed a series of neurofibroma and MPNST genetically engineered mouse (GEM) models that recapitulate the progressive nature of human PNST. These newly developed GEM neurofibroma and MPNST models, for the first time, enable us to assess the role of a critical molecular pathway(s) and therapeutic effects of an anti-tumor agent(s) during all stages of PNST development. Particularly, we have identified critical cellular and molecular events in the earliest stages of PNST development. Based upon our preliminary data, we hypothesize that the mammalian target of rapamycin complex 1 (mTORC1) activity is not always elevated, but instead dynamically regulated during initiation, progression, and malignant transformation of PNST. The objectives of this proposal are to systematically examine the role of mTORC1 signaling and therapeutic effects of rapamycin in the initiation, progression, and malignant transformation of PNST. These studies aim to identify potential therapeutic windows that can target plexiform neurofibroma and MPNST at the earliest stages. Specifically, we will (1) determine phenotypic consequences of inhibition of mTORC1 signaling during early phases of peripheral nerve sheath tumor development and (2) determine the role of dynamically regulated mTORC1 activity in peripheral nerve sheath tumor development. This proposal not only will provide important insights into the role of the mTORC1-mediated signaling pathway in all stages of PNST development, but also will systematically assess therapeutic effects of rapamycin in the initiation, progression and malignant transformation of PNST. PUBLIC HEALTH RELEVANCE: Benign and malignant peripheral nerve sheath tumors (PNST) are major sources of NF1-associated morbidity and mortality. This proposal not only will provide important insights into the role of the mTORC1-mediated signaling pathway in all stages of PNST development, but also will systematically assess therapeutic effects of rapamycin in the initiation, progression and malignant transformation of PNST.